Molding of a polymer

ABSTRACT

The invention relates to a process for molding a copolymer of a polyalkylene glycol terephthalate and an aromatic ester, comprising the steps of: a) preparing a solution of the copolymer in a suitable first solvent; and b) forming a gel of the solution.

[0001] The invention relates to a process for molding a polymer. More inparticular, the invention relates to a process for molding a copolymerof a polyalkylene glycol terephtalate and an aromatic ester.

[0002] Copolymers of a polyalkylene glycol terephtalate and an aromaticesters have been found to possess highly favorable properties, such asbiodegradability and biocompatibility. For these reasons, they arefinding application in tissue engineering applications, such as in thefunction of scaffolds for seeding cells of different types.Particularly, copolymers of polyethylene glycol terephtalate (PEGT) andpolybutylene terephthalate, which are known under the name ofPolyactive®, have been found to give promising results in this regard.

[0003] In order for the copolymers to be suitable for use in theseapplications, it is necessary that their shape can be efficientlycontrolled. Solid bodies of different shapes can be formed of thesecopolymers, and in fact of polymers in general, in several ways.Well-known examples include injection molding and extrusion.

[0004] Most methods for giving a desired shape to a polymer materialcomprise the step of preparing a melt of the polymer so that it can beformed into the desired shape. Once formed into the desired shape, it ishardened or cured. In order to prepare the melt it is usually necessaryto work at the very high temperatures required for obtaining a melt.

[0005] Under certain circumstances, it is desired to be able to producea solid body of a polymer without subjecting it to the high temperaturesrequired for obtaining a melt. Often the thermal strain imposed on apolymeric material during extrusion is undesired. Particular (partial)oxidation of the polymeric material is to be avoided. It is accordinglyan object of the present invention to provide a method of molding acopolymer of a polyalkylene glycol terephtalate and an aromatic esterwhich leads in an efficient manner to a solid body of a desired shapeunder mild conditions.

[0006] Further, in particular in view of the above referred toapplications of the copolymers, it is often desired to be able toincorporate (bioactive) additives in the solid bodies to be formed. Forinstance, the presence of growth factors may be very much desired inorder to enhance cell growth or differentiation. As many of thesebioactive additives are very sensitive compounds, the need for workingunder mild conditions becomes even more important. It is thus a furtherobject of the invention to provide a method for molding a copolymer of apolyalkylene glycol terephtalate and an aromatic ester under mildconditions, which method can conveniently be adapted in order toincorporate additives into the solid body to be formed.

[0007] Surprisingly, it has now been found that the properties ofcopolymers of a polyalkylene glycol terephtalate and an aromatic estermake it possible to produce solid bodies of them in a gel moldingprocess. Accordingly, the invention relates to a process for molding acopolymer of a polyalkylene glycol terephtalate and an aromatic ester,comprising the steps of:

[0008] a) preparing a solution of the copolymer in a suitable firstsolvent; and

[0009] b) forming a gel of the solution.

[0010] The present process does not involve the preparation of a melt ofthe copolymer. It has been found that, in accordance with the invention,the copolymer may be molded into any desired shape under very mildconditions. The solvents used can advantageously be recovered andrecycled.

[0011] The copolymer which is formed into a solid body according to theinvention, is a copolymer of a polyalkylene glycol terephtalate and anaromatic polyester. Preferably, the copolymer comprises 20-90 wt. %,more preferably 40-70 wt. % of the polyalkylene glycol terephtalate, and80-10 wt. %, more preferably 60-30 wt. % of the aromatic polyester. Apreferred type of copolymers according to the invention is formed by thegroup of block copolymers.

[0012] The polyalkylene glycol terephtalate may have a weight averagemolecular weight of about 150 to about 4000. Preferably, thepolyalkylene glycol terephtalate has a weight average molecular weightof 200 to 1500. The aromatic polyester preferably has a weight averagemolecular weight of from 200 to 5000, more preferably from 250 to 4000.The weight average molecular weight of the copolymer preferably liesbetween 10,000 and 300,000, more preferably between 40,000 and 120,000.

[0013] The weight average molecular weight may suitably be determined bygel permeation chromatography (GPC) . This technique, which is known perse, may for instance be performed using chloroform as a solvent andpolystyrene as external standard. Alternatively, a measure for theweight average molecular weight may be obtained by using viscometry (seeNEN-EN-ISO 1628-1). This technique may for instance be performed at 25°C. using chloroform as a solvent. Preferably, the intrinsic viscosity ofthe copolymer lies between 0.2289 and 1.3282 dL/g, which corresponds toa weight average molecular weight between 10,000 and 200,000. Likewise,the more preferred ranges for the, weight average molecular weightmeasured by GPC mentioned above can also be expressed in terms of theintrinsic viscosity.

[0014] In a preferred embodiment, the polyalkylene glycol terephtalatecomponent has units of the formula -OLO-CO-Q-CO-, wherein O representsoxygen, C represents carbon, L is a divalent organic radical remainingafter removal of terminal hydroxyl groups from apoly(oxyalkylene)glycol, and Q is a divalent organic radical.

[0015] Preferred polyalkylene glycol terephtalates are chosen from thegroup of polyethylene glycol terephzalate, polypropylene glycolterephtalate, and polybutylene glycol terephtalate and copolymersthereof, such as poloxamers. A highly preferred polyalkylene glycolterephtalate is polyethylene glycol terephtalate.

[0016] The terms alkylene and polyalkylene generally refer to anyisomeric structure, i.e. propylene comprises both 1,2-propylene and1,3-propylene, butylene comprises 1,2-butylene, 1,3-butylene,2,3-butylene, 1,2-isobutylene, 1,3-isobutylene and 1,4-isobutylene(tetramethylene) and similarly for higher alkylene homologues. Thepolyalkylene glycol terephtalate component is preferably terminated witha dicarboxylic acid residue -CO-Q-CO-, if necessary to provide acoupling to the polyester component. Group Q may be an aromatic grouphaving the same definition as R, or may be an aliphatic group such asethylene, propylene, butylene and the like.

[0017] The polyester component preferably has units -O-E-O-CO-R-CO-,wherein O represents oxygen, C represents carbon, E is a substituted orunsubstituted alkylene or oxydialkylene radical having from 2 to 8carbon atoms, and R is a substituted or unsubstituted divalent aromaticradical.

[0018] In a preferred embodiment, the polyester is chosen from the groupof polyethylene terephthalate, polypropylene terephthalate, andpolybutylene terephthalate. A highly preferred polyester is polybutyleneterephthalate.

[0019] The preparation of the copolymer will now be explained by way ofexample for a polyethylene glycol terephtalate/polybutyleneterephthalate copolymer. Based on this description, the skilled personwill be able to prepare any desired copolymer within the above describedclass. An alternative manner for preparing polyalkylene glycolterephtalate/polyester copolymers is disclosed in U.S. Pat. No.3,908,201.

[0020] A polyethylene glycol terephtalate/polybutylene terephthalatecopolymer may be synthesized from a mixture of dimethyl terephthalate,butanediol (in excess), polyethylene glycol, an antioxidant and acatalyst. The mixture is placed in a reaction vessel and heated to about180° C., and methanol is distilled as transesterification proceeds.During the transesterification, the ester bond with methyl is replacedwith an ester bond with butylene and/or the polyethyene glycol. Aftertransesterification, the temperature is raised slowly to about 245° C.,and a vacuum (finally less than 0.1 mbar) is achieved. The excessbutanediol is distilled off and a prepolymer of butanediol terephthalatecondenses with the polyethylene glycol to form apolyethylene/polybutylene terephthalate copolymer. A terephthalatemoiety connects the polyethylene glycol units to the polybutyleneterephthalate units of the copolymer and thus such a copolymer also issometimes referred to as a polyethylene glycolterephthalate/polybutylene terephthalate copolymer (PEGT/PBT copolymer).

[0021] In accordance with the invention, the copolymer is firstdissolved in a suitable solvent, by which is meant that a substantiallyhomogeneous, one phase mixture is prepared of the copolymer and saidsuitable solvent. Depending on the nature of the copolymer and thesolvent, it may be necessary to work at elevated temperature in order todissolve the copolymer. However, the temperature required for this stepwill always be low in comparison with the temperature that would beneeded to prepare a melt of the copolymer. Thus, the present processallows the molding of the copolymer under mild conditions. Suitabletemperatures for preparing the solution will be below the boilingtemperature of the solvent, preferably between 20 and 200° C., morepreferably between 30 and 100° C.

[0022] The solvent to be used should be suitable for dissolving thecopolymer. Also, it should be possible to form the solution containingthe polymer into a gel. Solvents that have been found to be useful forthis purpose are relatively polar organic solvents. Preferred examplesate solvents with a relatively high boiling point, facilitatingdissolution of the copolymer. Particularly preferred areN-methylpyrrolidone, 1,4-dioxane, 1,3-dioxane, and combinations thereof.N-methylpyrrolidone is most preferred.

[0023] It is preferred that a relatively concentrated solution of thecopolymer is prepared in order to facilitate the formation of the gel.Preferably, the solution is prepared using such relative amounts ofcopolymer and solvent, that the solution comprises between 5 and 90 wt.%, preferably between 50 and 80 wt. %, of the copolymer, based on theweight of the solution.

[0024] The solution of the copolymer is subsequently transformed into agel. In this regard, the term ‘gel’ is intended to refer to a colloidalsolution. Upon the transformation of the solution of the copolymer intothe gel the viscosity will increase markedly. Preferably, the viscosityis so high that a moldable, dough-like solid is obtained. The gelformation may be accomplished by slightly cooling the solution. In casethe solution is prepared at elevated temperatures, it will generallysuffice to allow the solution to cool to room temperature. Generally, itis desired that the cooling will proceed faster than the gelification.

[0025] Before the solution is gelified, it is possible to mix additivesinto the solution, which will be incorporated into the gel, andconsequently also into the solid body to be formed. As at this stage thesolution will still have a relatively low viscosity, it is possible tohomogeneously distribute the additives throughout the solution.Accordingly, the additives will be present throughout the solid body tobe formed, in homogeneous fashion. In other words, the copolymer forms amatrix in which the additive or additives are homogeneously distributed.

[0026] The additives may vary widely in nature; in principle any type ofadditive may be incorporated as long as its nature or used amount doesnot obstruct with the gel-forming capacity of the copolymer. Dependingon the envisaged application of the solid body of the copolymer, theadditive may be chosen from the group of biologically active agents. Asthe copolymer is biodegradable in vivo the additives will be released tothe surroundings of the solid body in a controlled manner. This behaviorof the copolymer has previously been described in EP-A-0 830 859. Theseadditives may be added to the solution in amounts ranging from 0 to 50wt. %, preferably from 1 to 20 wt. %.

[0027] The term “biologically active agent”, as used herein, means anagent which provides a therapeutic or prophylactic effect. Such agentsinclude, but are not limited to, antimicrobial agents (includingantibacterial and anti-fungal agents), anti-viral agents, anti-tumoragents, hormones immunogenic agents, growth factors, lipids, andlipopolysaccharides.

[0028] Biologically active agents which may be incorporated include, butare not limited to, non-peptide, non-protein small-sized drugs. Theyhave a molecular weight which in general is less than 1500, and inparticular less than 500. A second important group of biologicallyactive agents are biologically active peptides and proteins.

[0029] Examples of non-peptide, non-protein small-sized drugs which maybe incorporated include, but are not limited to, the following:

[0030] 1. Anti-tumor agents: altretamin, fluorouracil, amsacrin,hydroxycarbamide, asparaginase, ifosfamid, bleomycin, lomustin,busulfan, melphalan, chlorambucil, mercaptopurin, chlormethin,methotrexate, cisplatin, mitomycin, cyclophosphamide, procarbazin,cytarabin, teniposid, dacarbazin, thiotepa, dactinomycin, tioguanin,daunorubicin, treosulphan, doxorubicin, tiophosphamide, estramucin,vinblastine, etoglucide, vincristine, etoposid, vindesin.

[0031] 2. Antimicrobial agents

[0032] 2.1 Antibiotics Penicillins: ampicillin, nafcillin, amoxicillin,oxacillin, azlocillin, penicillin G, carbenicillin, penicillin V,dicloxacillin, phenethicillin, floxacillin, piperacillin, mecillinam,sulbenicillin, methicillin, ticarcillin, mezlocillin Cephalosporins:cefaclor, cephalothin, cefadroxil, cephapirin, cefamandole, cephradine,cefatrizine, cefsulodine, cefazolin, cefLazidim, ceforanide, ceftriaxon,cefoxitin, cefuroxime, cephacetrile, latamoxef, cephalexinAminoglycosides: amikacin, neomycin, dibekacyn, kanamycin, gentamycin,netilmycin, kanamycin, tobramycin Macrolides: amphotericin B,novobiocin, bacitracin, nystatin, clindamycin, polymyxins, colistin,rovamycin, erythromycin, spectinomycin, lincomycin, vancomycinTetracyclines: chlortetracycline, oxytetracycline, demeclocycline,rolitetracycline, doxycycline, tetracycline, minocycline Otherantibiotics: chloramphenicol, rifamycin, rifampicin, thiamphenicol

[0033] 2.2 Chemotherapeutic agents Sulfonamides: sulfadiazine,sulfamethizol, sulfadimethoxin, sulfamethoxazole, sulfadimidin,sulfamethoxypyridazine, sulfafurazole, sulfaphenazol, sulfalene,sulfisomidin, sulfamerazine, sulfisoxazole, trimethoprim withsulfamethoxazole or sulfametrole Urinary tract antiseptics: methanamine,quinolones (norfloxacin, cinoxacin), nalidixic acid, nitro-compounds(nitrofurantoine, nifurtoinol) , oxolinic acid Anaerobic infections:metronidazole

[0034] 3. Drugs for tuberculosis: aminosalicyclic acid, isoniazide,cycloserine, rifampicine, ethamburol, tiocarlide, ethionamide, viomycin

[0035] 4. Drugs for leprosy: amithiozone, rifampicine, clofazimine,sodium sulfoxone, diaminodiphenylsulfone (DDS, dapsone)

[0036] 5. Antifungal agents: amphotericin B, ketoconazole, clotrimazole,miconazole, econazole, natamycin, flucytosine, nystatine, griseofulvin

[0037] 6. Antiviral agents: aciclovir, idoxuridine, amantidine,methisazone, cytarabine, vidarabine, ganciclovir

[0038] 7. Chemotherapy of amebiasis: chloroquine, iodoquinol,clioquinol, metronidazole, dehydroemetine, paromomycin, diloxanide,furoatetinidazole, emetine

[0039] 8. Anti-malarial agents: chloroquine, pyrimethamine,hydroxychloroquine, quinine, mefloquine, sulfadoxine/pyrimethamine,pentamidine, sodium suramin, primaquine, trimethoprim, proguanil

[0040] 9. Anti-helminthiasis agents: antimony potassium tartrate,niridazole, antimony sodium dimercaptosuccinate, oxamniquine, bephenium,piperazine, dichiorophen, praziquantel, diethylcarbamazine, pyrantelparmoate, hycanthone, pyrivium pamoate, levamisole, stibophen,mebendazole, tetramisole, metrifonate, thiobendazole, niclosamide

[0041] 10. Anti-inflammatory agents: acetylsalicyclic acid, mefenamicacid, aclofenac, naproxen, azopropanone, niflumic acid, benzydamine,oxyphenbutazone, diclofenac, piroxicam, fenoprofen, pirprofen,flurbiprofen, sodium salicyclate, ibuprofensulindac, indomethacin,tiaprofenic acid, ketoprofen, tolmetin

[0042] 11. Anti-gout agents: colchicine, allopurinol

[0043] 12. Centrally acting (opoid) analgesics: alfentanil, methadone,bezitramide, morphine, buprenorfine, nicomorphine, butorfanol,pentazocine, codeine, pethidine, dextromoramide, piritranide,dextropropoxyphene, sufentanil, fentanyl

[0044] 13. Local anesthetics: articaine, mepivacaine, bupivacaine,prilocaine, etidocaine, procaine, lidocaine, tetracaine

[0045] 14. Drugs for Parkinson's disease: amantidine, diphenhydramine,apomorphine, ethopropazine, benztropine mesylate, lergotril, biperiden,levodopa, bromocriptine, lisuride, carbidopa, metixen, chlorphenoxamine,orphenadrine, cycrimine, procyclidine, dexetimide, trihexyphenidyl

[0046] 15. Centrally active muscle relaxants: baclofen, carisoprodol,chlormezanone, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam,febarbamate, mefenoxalone, mephenesin, metoxalone, methocarbamol,tolperisone

[0047] 16. Hormones and hormone antagonistics

[0048] 16.1 Corticosteroids

[0049] 16.1.1 Mineralocorticosteroids: cortisol, desoxycorticosterone,flurohydrocortisone

[0050] 16.1.2 Glucocorticosteroids: beclomethasone, betamethasone,cortisone, dexamethasone, fluocinolone, fluocinonide, fluocortolone,fluorometholone, fluprednisolone, flurandrenolide, halcinonide,hydrocortisone, medrysone, methylprednisolone, paramethasone,prednisolone, prednisone, triamcinolone (acetonide)

[0051] 16.2 Androgens

[0052] 16.2.1 Androgenic steroids used in therapy: danazole,fluoxymesterone, mesterolone, methyltestosterone, testosterone and saltsthereof

[0053] 16.2.2 Anabolic steroids used in therapy: calusterone, nandroloneand salts thereof, dromostanolone, oxandrolone, ethylestrenol;oxymetholone, methandriol, stanozolol methandrostenolone, testolactone

[0054] 16.2.3 Antiandrogens: cyproterone acetate

[0055] 16.3 Estrogens

[0056] 16.3.1 Estrogenic steroids used in therapy: diethylstilbestrol,estradiol, estriol, ethinylestradiol, mestranol, quinestrol

[0057] 16.3.2 Anti-estrogens: chlorotrianisene, clomiphene,ethamoxytriphetol, nafoxidine, tamoxifen

[0058] 16.4 Progestins: allylestrenol, desogestrel, dimethisterone,dydrogesterone, ethinylestrenol, ethisterone, ethynadiol diacetate,etynodiol, hydroxyprogesterone, levonorgestrel, lynestrenol,medroxyprogesterone, megestrol acetate, norethindrone, norethisterone,norethynodrel, norgestrel, progesterone

[0059] 17. Thyroid drugs

[0060] 17.1 Thyroid drugs used in therapy: levothyronine, liothyronine

[0061] 17.2 Anti-thyroid drugs used in therapy: carbimazole,methimazole, methylthiouracil, propylthiouracil

[0062] When a non-peptide, non-protein, small-sized drug, such as thosedescribed above, is to be incorporated, the polyalkylene glycolterephtalate component of the copolymer preferably has a molecularweight of from about 200 to 400. Also, the polyalkylene glycolterephtalate component is present in the copolymer in an amount of from20 wt. % to 90 wt. % of the weight of the copolymer, preferably fromabout 40 wt. % to about 70 wt. % of the weight of the copolymer. Ingeneral, the aromatic polyester is present in the copolymer in an amountof from 10 wt. % to 80 wt. % of the copolymer, preferably in an amountof from about 30 wt. % to about 60 wt. % of the copolymer.

[0063] When a hydrophobic small-sized drug, such as, for example, asteroid hormone is incorporated, preferably at least one hydrophobicantioxidant is present. Hydrophobic antioxidants which may be employedinclude, but are not limited to, tocopherols, such as α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, ε-tocopherol, ζ₁-tocopherol,ζ₂-tocopherol, and η-tocopherol; and 1-ascorbic acid 6-palmitate. Suchhydrophobic anzioxidants retard the degradation of the copolymer andretard the release of the biologically active agent. Thus, the use of ahydrophobic or lipophilic antioxidant is applicable particularly to theformation of matrices which include drugs which tend to be releasedquickly from the microspheres, such as, for example, small drugmolecules having a molecular weight less than 500. The at least onehydrophobic antioxidant may be present in the matrix in an amount offrom about 0.1 wt. % to about 10 wt. % of the total weight of thematrix, preferably from about 0.5 wt. % to about 2 wt. %.

[0064] When the matrix includes a hydrophilic small-sized drug, such asan aminoglycoside, the matrix may also include, in addition to thehydrophobic antioxidant, a hydrophobic molecule such as cholesterol,ergosterol, lithocholic acid, cholic acid, dinosterol, betuline, oroleanolic acid, which may be employed in order to retard the releaserate of the agent from the copolymer matrix. Such hydrophobic moleculesprevent water penetration into the matrix, but do not compromise thedegradability of the matrix. In addition, such molecules have meltingpoints from 150° C. to 200° C. or decreases the matrix diffusioncoefficient for the biologically active agent, such as small drugmolecule, to be released. Thus, such hydrophobic molecules provide for amore sustained release of a biologically active agent from the matrix.The at least one hydrophobic molecule may be present in the matrix in anamount of from about 0.1 wt. % to about 20 wt. %, preferably from 1.0wt.% to 5.0 wt. %.

[0065] If it is desired to increase the hydrophilicity of the polymer,and thereby increase the degradation rate and drug releasing rate of thecopolymer, the copolymer may be modified by partially replacing thearomatic moiety with an aliphatic moiety such as succinate and/or byreplacing partially the alkylene with dioxyethylene. For example,terephthalate can be replaced by succinate in an amount of from about0.1 mole % to about 20 mole %, preferably from about 0.1 mole % to about5 mole %, by partially replacing dimethyl terephthalate as a startingcomponent with dimethyl succinate. As another example, butylene isreplaced with oxydiethylene in an amount of from about 0.1 mole % toabout 20 mole %, preferably from about 0.5 mole % to about 2 mole %, byreplacing 1,4-butanediol with dimethyleneglycol as a starting component.

[0066] Examples of peptides or proteins which may advantageously becontained in the matrix include, but are not limited to, immunogenicpeptides or immunogenic proteins, which include, but are not limited to,the following:

[0067] Growth factors: bone morphogenetic proteins, transforming growthfactors, fibroblast growth factors, epidermal growth factors, etc.Toxins: diphtheria toxin, tetanus toxin Viral surface antigens or partsof viruses: adenoviruses, Epstein-Barr Virus, Hepatitis A Virus,Hepatitis B Virus, Herpes viruses, HIV-1, HIV-2, HTLV-III, Influenzaviruses, Japanese encephalitis virus, Measles virus, Papilloma viruses,Paramyxoviruses, Polio Virus, Rabies, Virus, Rubella Virus, Vaccinia(Smallpox) viruses, Yellow Fever Virus Bacterial surface antigens orparts of bacteria: Bordetella pertussis, Helicobacter pylori,Clostridium tetani, Corynebacterium diphtheria, Escherichia ccli,Haemophilus influenza, Klebsiella species, Legionella pneumophila,Mycobacterium bovis, Mycobacterium leprae, Mycrobacterium tuberculosis,Neisseria gonorrhoeae, Neisseria meningitidis, Proteus species,Pseudomonas aeruginosa, Salmonella species, Shigella species,staphylococcus aureus, Streptococcus pyogenes, Vibrio cholera, Yersiniapestis Surface antigens of parasites causing disease or portions ofparasites: Plasmodium vivax - malaria, Plasmodium falciparum - malaria,Plasmodium ovale - malaria, Plasmodium malariae - malaria, Leishmaniatropica - leishmaniasis, Leishmania donovani, leishmaniasis, Leishmaniabranziliensis - leishmaniasis, Trypanosoma rhodescense - sleepingsickness, Trypanosoma gambiense - sleeping sickness, Trypanosoma cruzi -Chagas' disease, Schistosoma mansoni - schistosomiasis, Schistosomomahaematobium - schistomiasis, Schistosoma japonicum - shichtomiasis,Trichinella spiralis - trichinosis, Stronglyloides duodenale - hookworm,Ancyclostoma duodenale - hookworm, Necator americanus - hookworm,Wucheria bancrofti - filariasis, Brugia malaya - filariasis, Loa loa -filariasis, Dipetalonema perstaris - filariasis, Dracuncula medinensisfilariasis, Onchocerca volvulus - filariasis Immunoglobulins: IgG, IgA,IgM, Antirabies immunoglobulin, Antivaccinia immunoglobulin Antitoxins:Botulinum antitoxin, diphtheria antitoxin, gas gangrene antitoxin,tetanus antitoxin.

[0068] Other peptides or proteins which may be encapsulated include, butare not limited to, antigens which elicit an immune response againstFoot and Mouth Disease, hormones and growth factors such as folliclestimulating hormone, prolactin, angiogenin, epidermal growth factor,calcitonin, erythropoietin, thyrotropic releasing hormone, insulin,growth hormones, insulin-like growth factors 1 and 2, skeletal growthfactor, human chorionic gonadotropin, luteinizing hormone, nerve growthfactor, adrenocorticotropic hormone (ACTH), luteinizing hormonereleasing hormone (LHRH) parathyroid hormone (PTH) , thyrotropinreleasing hormone (TRH), vasopressin, cholecystokinin, and corticotropinreleasing hormone; cytokines, such as interferons, interleukins, colonystimulating factors, and tumor necrosis factors: fibrinolytic enzymes,such as urokinase, kidney plasminogen activator; and clotting factors,such as Protein C, Factor VIII, Factor IX, Factor VII and AntithrombinIII. Examples of other proteins or peptides which may be encapsulatedinclude, but are not limited to, albumin, atrial natriuretic factor,renin, superoxide dismutase, α₁-antitrypsin, lung surfactant proteins,bacitracin, bestatin, cydosporine, delta sleep-inducing peptide (DSIP),endorphins, glucagon, gramicidin, melanocyte inhibiting factors,neurotensin, oxytocin, somostatin, terprotide, serum thymide factor,thymosin, DDAVP, dermorphin, Met-enkephalin, peptidoglycan, satietin,thymopentin, fibrin degradation product, des-enkephalin-α-endorphin,gonadotropin releasing hormone, leuprolide, α-MSH, and metkephamid. Itis to be understood, however, that the scope of the present invention isnot limited to any specific peptides or proteins.

[0069] It has also been found to incorporate additives of a moreconstructive nature into the solid body of the copolymer. Thus, theinvention also provides a method for preparing composite materials atroom temperature. Particular suitable additives in this regard areceramic materials. Preferred examples of such ceramic materials arecalcium phosphates those which are both sufficiently biocompatible andsufficiently biodegradable to be used as an implant in living tissue canbe used. Preferred calcium phosphates are octacalcium phosphate,apatites, such as hydroxyapatite and carbonate apatite, whitlockites,such as α-tricalcium phosphate and β-tricalcium phosphate, andcombinations thereof. These ceramics may be added to the solution inamounts ranging from 0 to 75 wt. %, preferably from 40 to 60 wt. %.

[0070] As has been mentioned above, the solution, optionally comprisingone or more of the above additives, is formed into a gel, which mayconveniently be done by slightly cooling the solution. In case thesolution is prepared at elevated temperature, as is preferred, it willusually suffice to allow the solution to cool to room temperature.

[0071] The thus obtained gel may subsequently be formed into a solidbody by removing the suitable first solvent. Depending on the nature ofthe suitable first solvent, one manner of doing this is by freezedrying.A different way of removing the first suitable solvent is by placing thegel in a second suitable solvent. The nature of the second suitablesolvent is to be chosen such that the first suitable solvent dissolvesreadily in it. Also, it is important that the copolymer itself does notdissolve in the second suitable solvent. Accordingly, by placing the gelin the second suitable solvent, the first solvent present in the gelwill migrate into the second solvent, leaving a solid body of thecopolymer. Examples of suitable solvents include water and aqueoussolutions, such as body fluids, ethanol and isopropanol.

[0072] As the second solvent can be composed of body fluids, it is alsopossible to use the gel as such and inject it into a patient's body. Thefirst solvent will migrate into the body fluids and be removed by thepatient's circulatory systems. Of course, care should be taken that thefirst solvent used is biocompatible. Upon the migration of the firstsolvent, the gel will harden and be transformed into a solid body. Theuse of the injectable gel is highly advantageous in many applications infor instance Qrthopedic or corrective surgery. Due to the advantageousproperties of the copolymer, it is envisaged that the gel may beinjected into bone defects or used in meniscus repair.

[0073] It is further possible to use the gel in a spinning or injectionmolding apparatus, for instance to produce fibers of the material.

[0074] It has been found that any additive, such as a biologicallyactive agent which was incorporated into the gel will substantiallyentirely remain in the copolymer matrix during the transformation of thegel into a solid body if so desired. Of course, in certain cases theadditive will not completely dissolve in the gel, and a two phase systemis obtained. Advantageously, it has been found that the solid body thatis formed upon immersing into the second solution will havesubstantially the same shape as the gel itself. Although a smallreduction in size may be encountered, the skilled person will have noproblems adjusting the dimensions of the gel to these circumstances.

[0075] The amount of the second solvent to be used can be easilyoptimized by the person skilled in the art. Generally, sufficientsolvent should be used for the gel to be immersed in. Also, there shouldbe a sufficient amount of the second solvent for the first solventpresent in the gel to essentially completely dissolve in said secondsolvent. Typical amounts of the second solvent will be at least 300 vol.%, with respect to the volume of the gel.

[0076] The solid body formed may have various applications. It has beenfound to be particular useful to function in the field of surgicaldevices and aids, such as bone filler cement. In addition it has beenfound that the present solid body leads to very good results in thefield of tissue engineering, where it may be used as scaffold forseeding cells onto.

[0077] The invention will now be elucidated by the following,non-restrictive examples.

EXAMPLE 1

[0078] In a beaker, 100 grams of a copolymer of polyethylene glycolterephtalate (PEGT, M_(w)=1148) and polybutylene terephthalate (PBT),wherein the weight ratio of PEGT to PBT was 60 to 40, were dissolved in200 ml N-methylpyrrolidone (NMP) at a temperature of 100° C. by manualstirring. After approximately 30 minutes, a homogeneous solution wasobtained.

[0079] The solution was allowed to cool to room temperature, upon whicha gel was formed. The gel was cut from the beaker and placed in acontainer holding 5 liters of demineralized water. The NMP shifted fromthe gel into the water and a solid material was formed, which showedexcellent mechanical properties in a dry state and in a wet state.

EXAMPLE 2

[0080] The procedure of example 1 was repeated, except that about 100 mlof hydroxyapatite was added to the solution before cooling to roomtemperature.

[0081] After placement of the gel in demineralized water, a homogeneouscomposite of the copolymer and hydroxyapatite was formed. The materialshowed excellent mechanical properties in dry and wet condition.

EXAMPLE 3

[0082] The procedure of example 1 was repeated except that about 100 mlof sodium citrate was added to the solution before cooling to roomtemperature.

[0083] After placement of the gel in ethanol, a polymeric matrix of thecopolymer was obtained, in which matrix the sodium citrate washomogeneously distributed. The material showed excellent mechanicalproperties in dry and wet condition.

1. A process for molding a copolymer of a polyalkylene glycolterephtalate and an aromatic ester, comprising the steps of a) preparinga solution of the copolymer in a suitable first solvent; and b) forminga gel of the solution.
 2. A process according to claim 1, wherein thefirst solvent is chosen from the group of N-methylpyrrolidone,1,4-dioxane, 1,3-dioxane, and combinations thereof.
 3. A processaccording claim 1 or 2 wherein the solution is prepared at a temperatureof 20-200° C.
 4. A process according to any of the preceding claims,wherein the solution comprises between 5 and 90 wt. %, based on theweight of the solution, of the copolymer.
 5. A process according to anyof the preceding claims, wherein an additive is added to the solution,which additive is chosen from the group of calcium phosphates andbiologically active agents.
 6. A gel obtainable by a process accordingto any of the preceding claims.
 7. A process according to any of claims1-5, wherein the gel is placed in a second suitable solvent to obtain asolid body of the copolymer.
 8. A process according to claim 7, whereinthe second solvent is chosen from the group of water, ethanol,isopropanol, body fluids, and combinations thereof.
 9. A processaccording to claim 7 or 8, wherein the gel is placed in an amount of atleast 300 vol. %, with respect to the volume of the gel, of the secondsolvent.
 10. A process according to any of claims 1-6, wherein the gelis freezedried to obtain a solid body of the copolymer.
 11. A solid bodyobtainable by a process according to any of the claims 7-10.
 11. The useof a solid body according to claim 10 as a scaffold for tissueengineering or a bone filler cement.